Curating clinically relevant transcripts for the interpretation of sequence variants

Publication date: Available online 8 August 2018Source: The Journal of Molecular DiagnosticsAuthor(s): Marina T. DiStefano, Sarah E. Hemphill, Brandon J. Cushman, Mark J. Bowser, Elizabeth Hynes, Andrew R. Grant, Rebecca K. Siegert, Andrea M. Oza, Michael A. Gonzalez, Sami S. Amr, Heidi L. Rehm, Ahmad N. Abou TayounAbstractVariant interpretation depends on accurate annotations using biologically relevant transcripts. We have developed a systematic strategy for designating primary transcripts, and applied it to 109 hearing loss–associated genes that were divided into three categories. Category 1 genes (n=38) had a single transcript, Category 2 genes (n=32) had multiple transcripts, but a single transcript was sufficient to represent all exons, and Category 3 genes (n=38) had multiple transcripts with unique exons. Transcripts were curated with respect to gene expression reported in the literature and the Genotype-Tissue Expression Project. In addition, high frequency loss of function variants in the Genome Aggregation Database, and disease-causing variants in ClinVar and the Human Gene Mutation Database across the 109 genes were queried. These data were used to classify exons as "clinically significant", "uncertain significance", or "clinically insignificant". Interestingly, 6% of all exons, containing 124 "clinically significant" variants, were of “uncertain significance”. Finally, we used exon-level next generation sequencing quality metrics generated at two clinical l...
Source: The Journal of Molecular Diagnostics - Category: Pathology Source Type: research